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Circulating insulin-like growth factor I (IGF-I) is positively associated with the risks of colorectal, breast, and prostate cancer, but evidence for other less common cancers is limited. In this study, we investigated associations between serum IGF-I concentrations and incidence of less common cancers in the UK Biobank study. To enable comparison of effect estimates, and as positive controls, both common and less common cancer sites (total 30) were included in an outcome-wide analysis. Data from 394,388 cancer-free participants in the UK Biobank study were analyzed. Multivariable adjusted Cox proportional hazards models were used to determine associations between baseline serum IGF-I concentrations and cancer incidence, using repeated IGF-I measurements from up to 14,149 participants to correct for regression dilution bias. Higher IGF-I concentration was associated with increased risks of thyroid cancer [HR per 5 nmol/L higher concentration 1.18; 95% confidence interval (CI), 1.01–1.37] in addition to colorectal (HR, 1.08; 95% CI, 1.03–1.13), breast (HR, 1.11; 95% CI, 1.07–1.15), and prostate cancer (HR, 1.08; 95% CI, 1.05–1.12), and reduced risks of ovarian and liver cancer. Mean follow-up was 6.9 years and the possibility that the observed associations may be influenced by reverse causality bias cannot be excluded. Additional nominally significant associations with malignant melanoma, multiple myeloma, oral cancer, and esophageal squamous cell carcinoma did not survive correction for multiple testing. Studies with longer follow-up and pooled analyses are needed to further assess how broad the role of IGF-I is in cancer development.Significance:The results from this outcome-wide analysis are consistent with a positive association of IGF-I with cancers at several sites.

Supplementary Tables S1-3 and Figures S1-3. Table S1: Median, interquartile range (IQR), minimum (Min.) and maximum (max.) of follow-up time by cancer site. Table S2: Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer risk according to circulating insulin-like growth factor-I concentrations. Table S3: Hazard ratios (HRs) and 95% confidence intervals (CIs) of cancer risk according to circulating insulin-like growth factor-I concentrations stratified by follow-up time, sex and age-group. Figure S1: Flow diagram for reaching the analytical sample. Figure S2: Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk per 5 nmol/l higher insulin-like growth factor-I concentration by cancer site and sex. Figure S3: Hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer risk per 5 nmol/l higher insulin-like growth factor-I concentration by cancer site and age (

Background:Exposure to higher levels of melatonin may be associated with lower breast cancer risk, but epidemiologic evidence has been limited. We examined the relationship in a case–control study nested within the Diagnostisch Onderzoek Mammacarcinoom (DOM) study and conducted a meta-analysis of prospective studies.Methods:Concentrations of 6-sulfatoxymelatonin (aMT6s) in prediagnostic first morning urine voids were measured in 274 postmenopausal women diagnosed with breast cancer and 274 matched controls from the DOM study. Conditional logistic regression models were used to estimate multivariable adjusted ORs of breast cancer for thirds of aMT6s. Meta-analysis of this and previous prospective studies of urinary melatonin with breast cancer risk estimated the inverse-variance weighted averages of study-specific log RRs of breast cancer for the highest versus lowest levels of aMT6s.Results:In the DOM study, the ORs of breast cancer for the middle and highest versus lowest thirds of aMT6s were 0.70 [95% confidence interval (CI), 0.45–1.09] and 0.72 (95% CI, 0.44–1.19), respectively. In the meta-analysis of the DOM study with six previous studies (2,296 cases), RR of breast cancer for the highest versus lowest levels of aMT6s was 0.87 (95% CI, 0.76–1.01).Conclusions:Results from the DOM study, together with the published prospective data, do not support a strong association of melatonin with breast cancer risk.Impact:This study adds to the relatively scarce prospective data on melatonin in relation to breast cancer risk. The totality of the prospective evidence does not clearly show an association between melatonin and breast cancer risk, but further data are needed to be able to exclude a modest association.

BackgroundRed and processed meat has been consistently associated with risk for colorectal cancer, but evidence for other cancer sites is limited and few studies have examined the association between poultry intake and cancer risk. We examined associations between total meat, red meat, processed meat and poultry intake and incidence for 20 common cancer sites.Methods and FindingsWe analysed data from 475,023 participants (54% women) in UK Biobank. Participants were aged 37-73 years and cancer free at baseline. Information on meat consumption was based on a touchscreen questionnaire completed at baseline covering type and frequency of meat intake. Diet intake was re-measured a minimum of three times in a subsample (15%) using a web-based 24h dietary recall questionnaire. Multivariable-adjusted Cox proportional hazards models were used to determine the association between baseline meat intake and cancer incidence. Trends in risk across baseline meat intake categories were calculated by assigning a mean value to each category using estimates from the re-measured meat intakes. During a mean follow-up of 6.9 years, 28,955 participants were diagnosed with a malignant cancer. Total, red and processed meat intakes were each positively associated with risk of colorectal cancer (e.g. hazard ratio (HR) per 70 g/day higher intake of red and processed meat combined 1.31, 95%-confidence interval (CI) 1.14-1.52).Red meat intake was positively associated with breast cancer (HR per 50 g/day higher intake 1.12, 1.01-1.24) and prostate cancer (1.15, 1.03-1.29). Poultry intake was positively associated with risk for cancers of the lymphatic and hematopoietic tissues (HR per 30g/day higher intake 1.16, 1.03-1.32). Only the associations with colorectal cancer were robust to Bonferroni correction for multiple comparisons. Study limitations include unrepresentativeness of the study sample for the UK population, low case numbers for less common cancers and the possibility of residual confounding.ConclusionsHigher intakes of red and processed meat were associated with a higher risk of colorectal cancer. The observed positive associations of red meat consumption with breast and prostate cancer, and poultry intake with cancers of the lymphatic and hematopoietic tissues, require further investigation.

Publisher Copyright: © 2022 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC. Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged

ImportanceHigher physical activity levels are associated with lower risks of cancer, cardiovascular disease, and diabetes, but associations with many common and less severe health conditions are not known. These conditions impose large health care burdens and reduce quality of life.ObjectivesTo investigate the association between accelerometer-measured physical activity and the subsequent risk of hospitalization for 25 common reasons for hospitalization and to estimate the proportion of these hospitalizations that might have been prevented if participants had higher levels of physical activity.Design, Setting, and ParticipantsThis prospective cohort study used data from a subset of 81 717 UK Biobank participants aged 42 to 78 years. Participants wore an accelerometer for 1 week (between June 1, 2013, and December 23, 2015) and were followed up over a median (IQR) of 6.8 (6.2-7.3) years; follow-up for the current study ended in 2021 (exact date varied by location).ExposuresMean total and intensity-specific accelerometer-measured physical activity.Main Outcomes and MeasuresHospitalization for the most common health conditions. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% CIs for mean accelerometer-measured physical activity (per 1-SD increment) and risks of hospitalization for 25 conditions. Population-attributable risks were used to estimate the proportion of hospitalizations for each condition that might be prevented if participants increased their moderate to vigorous physical activity (MVPA) by 20 minutes per day.ResultsAmong 81 717 participants, the mean (SD) age at accelerometer assessment was 61.5 (7.9) years; 56.4% were female, and 97.0% self-identified as White. Higher levels of accelerometer-measured physical activity were associated with lower risks of hospitalization for 9 conditions: gallbladder disease (HR per 1 SD, 0.74; 95% CI, 0.69-0.79), urinary tract infections (HR per 1 SD, 0.76; 95% CI, 0.69-0.84), diabetes (HR per 1 SD, 0.79; 95% CI, 0.74-0.84), venous thromboembolism (HR per 1 SD, 0.82; 95% CI, 0.75-0.90), pneumonia (HR per 1 SD, 0.83; 95% CI, 0.77-0.89), ischemic stroke (HR per 1 SD, 0.85; 95% CI, 0.76-0.95), iron deficiency anemia (HR per 1 SD, 0.91; 95% CI, 0.84-0.98), diverticular disease (HR per 1 SD, 0.94; 95% CI, 0.90-0.99), and colon polyps (HR per 1 SD, 0.96; 95% CI, 0.94-0.99). Positive associations were observed between overall physical activity and carpal tunnel syndrome (HR per 1 SD, 1.28; 95% CI, 1.18-1.40), osteoarthritis (HR per 1 SD, 1.15; 95% CI, 1.10-1.19), and inguinal hernia (HR per 1 SD, 1.13; 95% CI, 1.07-1.19), which were primarily induced by light physical activity. Increasing MVPA by 20 minutes per day was associated with reductions in hospitalization ranging from 3.8% (95% CI, 1.8%-5.7%) for colon polyps to 23.0% (95% CI, 17.1%-28.9%) for diabetes.Conclusions and RelevanceIn this cohort study of UK Biobank participants, those with higher physical activity levels had lower risks of hospitalization across a broad range of health conditions. These findings suggest that aiming to increase MVPA by 20 minutes per day may be a useful nonpharmaceutical intervention to reduce health care burdens and improve quality of life.

Background Previous studies suggest that different foods rich in saturated fatty acids (SFA), particularly meat and dairy, have diverging directions of association with risks of total cardiovascular disease (CVD) and CVD subtypes.(1,2) Purpose To investigate the associations between SFA from different dietary sources and risks of total CVD, ischaemic heart disease (IHD), and stroke. Methods We analysed data on 114,285 UK Biobank participants who had completed ≥2 24-h dietary assessments and were free of CVD at the date of the latest 24-h dietary assessment. Risks of incident (non-fatal and fatal) total CVD, IHD and stroke by intakes of SFA from different sources were estimated using multivariable Cox regressions. Additional models assessed the role of body mass index (BMI) and low-density lipoprotein cholesterol (LDL-C) as potential mediators. We also estimated the associations between modelled isoenergetic substitution of 5% energy from SFA from meat with SFA from dairy, polyunsaturated fatty acids, monounsaturated fatty acids, carbohydrates from whole grains and carbohydrates from fruit and vegetables, and risk of CVD outcomes. A false discovery rate controlling procedure was used to account for multiple testing. Results Over a median 8.5 years of follow-up, there were 4,365, 3,394, and 1,041 cases of total CVD, IHD and stroke, respectively. There were no significant associations between total SFA intake and CVD outcomes. SFA from meat was positively associated with total CVD (hazard ratio for each 5% of energy, 1.19; 95% CI, 1.05–1.35) and IHD (1.21; 1.05–1.39) risk independently of lifestyle and cardiovascular risk factors. However, the estimates were attenuated and non-significant for both total CVD (1.11; 0.98–1.26) and IHD (1.12; 0.97–1.29) after adjustment for BMI. SFA from dairy was inversely associated with IHD risk (0.89; 0.82–0.96) in the multivariable model, however this finding was also attenuated after adjustment for BMI and did not pass correction for multiple testing (0.91; 0.84 to 0.98). Modelled replacement of 5% of energy from SFA from meat with carbohydrates from whole grains or carbohydrates from fruit and vegetables were associated with lower risk of stroke in the multivariable model (0.86; 0.78–0.94 & 0.86; 0.78–0.95, respectively) and the model adjusted for BMI and LDL-C (0.87; 0.79–0.96 & 0.86; 0.78–0.95, respectively). Conclusion(s) SFA from meat was associated with a higher risk of total CVD and IHD, while SFA from dairy was associated with lower risk of IHD, although BMI seemed to account for a large proportion of these associations. It is possible that diverging associations of SFA from different sources with CVD risk may explain the overall null association with total SFA observed in this study and some previous observational studies. Randomised controlled trials are needed to confirm whether replacing SFA from meat by carbohydrate from wholegrains or fruit and vegetables may be beneficial in reducing stroke risk. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Clarendon Fund and Jesus College Clarendon Old Members' AwardJesus College Graduate Scholarship

Insulin‐like growth factor‐I (IGF‐I) and testosterone have been implicated in prostate cancer aetiology. Using data from a large prospective full‐cohort with standardised assays and repeat blood measurements, and genetic data from an international consortium, we investigated the associations of circulating IGF‐I, sex hormone‐binding globulin (SHBG), and total and calculated free testosterone concentrations with prostate cancer incidence and mortality. For prospective analyses, risk was estimated using multivariable‐adjusted Cox regression in 199 698 male UK Biobank participants. Hazard ratios (HRs) were corrected for regression dilution bias using repeat hormone measurements from a subsample. Two‐sample Mendelian randomisation (MR) analysis of IGF‐I and risk used genetic instruments identified from UK Biobank men and genetic outcome data from the PRACTICAL consortium (79 148 cases and 61 106 controls). We used cis‐ and all (cis and trans) SNP MR approaches. A total of 5402 men were diagnosed with and 295 died from prostate cancer (mean follow‐up 6.9 years). Higher circulating IGF‐I was associated with elevated prostate cancer diagnosis (HR per 5 nmol/L increment = 1.09, 95% CI 1.05‐1.12) and mortality (HR per 5 nmol/L increment = 1.15, 1.02‐1.29). MR analyses also supported the role of IGF‐I in prostate cancer diagnosis (cis‐MR odds ratio per 5 nmol/L increment = 1.34, 1.07‐1.68). In observational analyses, higher free testosterone was associated with a higher risk of prostate cancer (HR per 50 pmol/L increment = 1.10, 1.05‐1.15). Higher SHBG was associated with a lower risk (HR per 10 nmol/L increment = 0.95, 0.94‐0.97), neither was associated with prostate cancer mortality. Total testosterone was not associated with prostate cancer. These findings implicate IGF‐I and free testosterone in prostate cancer development and/or progression., What's new? Testosterone, insulin‐like growth factor‐I (IGF‐I), and sex hormone‐binding globulin (SHBG) all have been associated with prostate‐cancer risk. In this large, prospective study, the authors analyzed how these circulating hormones might impact mortality as well as risk. They found that men with higher IGF‐I had a higher risk of both prostate‐cancer diagnosis and mortality. Men with higher free testosterone had an increased risk of prostate cancer, while men with higher SHBG had a decreased risk. These results support the roles of IGF‐I and testosterone in prostate cancer development.

Background There is limited prospective evidence on the association between meat consumption and many common, non-cancerous health outcomes. We examined associations of meat intake with risk of 25 common conditions (other than cancer). Methods We used data from 474,985 middle-aged adults recruited into the UK Biobank study between 2006 and 2010 and followed up until 2017 (mean follow-up 8.0 years) with available information on meat intake at baseline (collected via touchscreen questionnaire), and linked hospital admissions and mortality data. For a large sub-sample (~ 69,000), dietary intakes were re-measured three or more times using an online, 24-h recall questionnaire. Results On average, participants who reported consuming meat regularly (three or more times per week) had more adverse health behaviours and characteristics than participants who consumed meat less regularly, and most of the positive associations observed for meat consumption and health risks were substantially attenuated after adjustment for body mass index (BMI). In multi-variable adjusted (including BMI) Cox regression models corrected for multiple testing, higher consumption of unprocessed red and processed meat combined was associated with higher risks of ischaemic heart disease (hazard ratio (HRs) per 70 g/day higher intake 1.15, 95% confidence intervals (CIs) 1.07–1.23), pneumonia (1.31, 1.18–1.44), diverticular disease (1.19, 1.11–1.28), colon polyps (1.10, 1.06–1.15), and diabetes (1.30, 1.20–1.42); results were similar for unprocessed red meat and processed meat intakes separately. Higher consumption of unprocessed red meat alone was associated with a lower risk of iron deficiency anaemia (IDA: HR per 50 g/day higher intake 0.80, 95% CIs 0.72–0.90). Higher poultry meat intake was associated with higher risks of gastro-oesophageal reflux disease (HR per 30 g/day higher intake 1.17, 95% CIs 1.09–1.26), gastritis and duodenitis (1.12, 1.05–1.18), diverticular disease (1.10, 1.04–1.17), gallbladder disease (1.11, 1.04–1.19), and diabetes (1.14, 1.07–1.21), and a lower IDA risk (0.83, 0.76–0.90). Conclusions Higher unprocessed red meat, processed meat, and poultry meat consumption was associated with higher risks of several common conditions; higher BMI accounted for a substantial proportion of these increased risks suggesting that residual confounding or mediation by adiposity might account for some of these remaining associations. Higher unprocessed red meat and poultry meat consumption was associated with lower IDA risk.

Metabolomics may help to elucidate mechanisms underlying diet-disease relationships and identify novel risk factors for disease. To inform the design and interpretation of such research, evidence on diet-metabolite associations and cross-assay comparisons is needed. We aimed to compare nuclear magnetic resonance (NMR) metabolite profiles between meat-eaters, fish-eaters, vegetarians and vegans, and to compare NMR measurements to those from mass spectrometry (MS), clinical chemistry and capillary gas-liquid chromatography (GC). We quantified 207 serum NMR metabolite measures in 286 male participants of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford cohort. Using univariate and multivariate analyses, we found that metabolite profiles varied by diet group, especially for vegans, the main differences compared to meat-eaters were lower levels of docosahexaenoic acid, total n-3 and saturated fatty acids, cholesterol and triglycerides in very-low-density lipoproteins, various lipid factions in high-density lipoprotein, sphingomyelins, tyrosine and creatinine, and higher levels of linoleic acid, total n-6, polyunsaturated fatty acids and alanine. Levels in fish-eaters and vegetarians differed by metabolite measure. Concentrations of 13 metabolites measured using both NMR and MS, clinical chemistry or GC were mostly similar. In summary, vegans’ metabolite profiles were markedly different to those of men consuming animal products. The studied metabolomics platforms are complementary, with limited overlap between metabolite classes.

Background Although prostate cancer is a leading cause of cancer death, its aetiology is not well understood. We aimed to identify novel biochemical factors for prostate cancer incidence and mortality in UK Biobank. Methods A range of cardiovascular, bone, joint, diabetes, renal and liver-related biomarkers were measured in baseline blood samples collected from up to 211,754 men at recruitment and in a subsample 5 years later. Participants were followed-up via linkage to health administrative datasets to identify prostate cancer cases. Hazard ratios (HRs) and 95% confidence intervals were calculated using multivariable-adjusted Cox regression corrected for regression dilution bias. Multiple testing was accounted for by using a false discovery rate controlling procedure. Results After an average follow-up of 6.9 years, 5763 prostate cancer cases and 331 prostate cancer deaths were ascertained. Prostate cancer incidence was positively associated with circulating vitamin D, urea and phosphate concentrations and inversely associated with glucose, total protein and aspartate aminotransferase. Phosphate and cystatin-C were the only biomarkers positively and inversely, respectively, associated with risk in analyses excluding the first 4 years of follow-up. There was little evidence of associations with prostate cancer death. Conclusion We found novel associations of several biomarkers with prostate cancer incidence. Future research will examine associations by tumour characteristics.

Background There is limited prospective evidence on possible differences in fracture risks between meat-eaters and vegetarians. We aimed to study this in a prospective cohort with a large proportion of non-meat eaters. Methods In EPIC-Oxford, dietary information was collected at baseline (1993–2001) and subsequently around 2010. Participants were categorised into five diet groups at both time points (with 20,106 regular meat-eaters: ≥50 g of meat per day, 9,274 low meat-eaters: Results Compared with regular meat-eaters, vegetarians had marginally higher risks of total fractures (hazard ratios 1.10; 95% confidence interval 1.00–1.20) and arm fractures (1.28; 1.01–1.63), while vegans had higher risks of total fractures (1.44; 1.21–1.72), arm fractures (1.60, 1.01–2.54) and leg fractures (2.06; 1.22–3.47). For hip fractures, the risks were significantly higher in fish-eaters (1.28; 1.03–1.59), vegetarians (1.27; 1.05–1.55) and vegans (2.35; 1.67–3.30) compared with regular meat-eaters. There were no significant differences in risks of wrist, ankle or other main site fractures by diet group. Overall, the significant associations appeared to be stronger before adjustment for BMI (e.g. 1.52; 1.27–1.81 in vegans for total fractures), and were slightly attenuated but remained significant with additional adjustment for dietary calcium and total protein. Conclusion Overall, non-meat eaters, especially vegans, had higher risks of either total or some site-specific fractures, particularly hip fractures, than regular meat eaters. These differences may be partially related to lower BMI or lower dietary intakes of calcium and protein in the non-meat eaters. Further studies of non-European and contemporary populations are needed to determine the generality of these findings.

Background Insulin-like growth factor-I (IGF-I) is suggested to support cancer cell growth and proliferation. Pre-diagnostic circulating IGF-I concentrations have been shown to be positively associated with breast cancer, prostate cancer and colorectal cancer but evidence for less common cancer sites is limited. The aim of this study was to investigate the associations between serum IGF-I concentrations and the incidence of rarer cancers using an outcome-wide approach to study cancers at 26 sites in UK Biobank, in which serum concentrations of IGF-I were measured for ~ 467,000 participants (93%). Methods We analysed data from 394,406 cancer-free participants (52% women). IGF-I was measured in serum collected at baseline and in a subsample of 14,149 participants again in repeat samples collected during follow-up. Cancer diagnosis and death due to cancer during follow-up were determined using data-linkage with cancer and death registries. Multivariable-adjusted Cox proportional hazards models were used to determine associations between baseline serum IGF-I concentrations and cancer incidence, using the repeated measurements to correct estimates for regression dilution. Results After a mean follow-up of 6.9 years, 23,496 participants were diagnosed with a malignant cancer. Higher IGF-I concentration was associated with an increased risk of colorectal cancer (hazard ratio per 5 nmol/l 1.10, 95%-CI 1.05–1.15), colon cancer (1.11, 1.05–1.17), malignant melanoma (1.08, 1.01–1.15), breast cancer in women (1.11, 1.07–1.15), prostate cancer (1.08, 1.04–1.11), thyroid cancer (1.23, 1.05–1.43) and multiple myeloma (1.13, 1.01–1.27), and a reduced risk of oral (0.86, 0.77–0.97), liver (0.37, 0.30–0.45), endometrial (0.90, 0.82–1.00) and ovarian cancer (0.88, 0.78–0.99). Conclusion Higher IGF-I concentrations were associated with higher risks of cancer at the established sites (breast, colorectal and prostate cancer) and malignant melanoma, thyroid cancer and multiple myeloma. Higher IGF-I concentrations were associated with lower risks of oral, liver, endometrial and ovarian cancer; longer follow-up is needed to investigate the possible role of reverse causality.

Circulating insulin-like growth factor I (IGF-I) is positively associated with the risks of colorectal, breast, and prostate cancer, but evidence for other less common cancers is limited. In this study, we investigated associations between serum IGF-I concentrations and incidence of less common cancers in the UK Biobank study. To enable comparison of effect estimates, and as positive controls, both common and less common cancer sites (total 30) were included in an outcome-wide analysis. Data from 394,388 cancer-free participants in the UK Biobank study were analyzed. Multivariable adjusted Cox proportional hazards models were used to determine associations between baseline serum IGF-I concentrations and cancer incidence, using repeated IGF-I measurements from up to 14,149 participants to correct for regression dilution bias. Higher IGF-I concentration was associated with increased risks of thyroid cancer [HR per 5 nmol/L higher concentration 1.18; 95% confidence interval (CI), 1.01–1.37] in addition to colorectal (HR, 1.08; 95% CI, 1.03–1.13), breast (HR, 1.11; 95% CI, 1.07–1.15), and prostate cancer (HR, 1.08; 95% CI, 1.05–1.12), and reduced risks of ovarian and liver cancer. Mean follow-up was 6.9 years and the possibility that the observed associations may be influenced by reverse causality bias cannot be excluded. Additional nominally significant associations with malignant melanoma, multiple myeloma, oral cancer, and esophageal squamous cell carcinoma did not survive correction for multiple testing. Studies with longer follow-up and pooled analyses are needed to further assess how broad the role of IGF-I is in cancer development. Significance: The results from this outcome-wide analysis are consistent with a positive association of IGF-I with cancers at several sites.

Background Previous studies suggest a protective role of physical activity in breast cancer risk, largely based on self-reported activity. We aimed to clarify this association by examining breast cancer risk in relation to self-reported physical activity, informed by accelerometer-based measures in a large subset of participants. Methods We analysed data from 47,456 premenopausal and 126,704 postmenopausal women in UK Biobank followed from 2006 to 2014. Physical activity was self-reported at baseline, and at resurvey in a subsample of 6443 participants. Accelerometer data, measured from 2013 to 2015, were available in 20,785 women. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated by using multivariable-adjusted Cox regression. Results A total of 3189 cases were diagnosed during follow-up (mean = 5.7 years). Women in the top compared with the bottom quartile of self-reported physical activity had a reduced risk of both premenopausal (RR 0.75; 95% CI 0.60–0.93) and postmenopausal breast cancer (RR 0.87; 95% CI 0.78–0.98), after adjusting for adiposity. In analyses utilising physical activity values assigned from accelerometer measurements, an increase of 5 milli-gravity was associated with a 21% (RR 0.79; 95% CI 0.66–0.95) reduction in premenopausal and a 16% (RR 0.84; 95% CI 0.73–0.96) reduction in postmenopausal breast cancer risk. Conclusions Greater physical activity is associated with a reduction in breast cancer risk, which appears to be independent of any association it may have on risk through its effects on adiposity.

Background Epidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses allowed for causal inference. Patients and methods We investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206 263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGF-binding protein-3 (IGFBP-3) levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122 977 cases and 105 974 controls. Results In the UK Biobank, after a median follow-up of 7.1 years, 4360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/l increment of IGF-1 = 1.11, 95% CI = 1.07–1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/l increment in genetically-predicted IGF-1 concentration was associated with a greater breast cancer risk (odds ratio = 1.05, 95% CI = 1.01–1.10; P = 0.02), with a similar effect estimate for estrogen-positive (ER+) tumours, but no effect found for estrogen-negative (ER−) tumours. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (odds ratio per 1-standard deviation increment = 1.00, 95% CI = 0.97–1.04; P = 0.98). Conclusion Our results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis., Highlights • We conducted complementary observational and Mendelian randomization (MR) analyses to investigate the role of circulating insulin-like growth factor-1 (IGF-1) in breast cancer development • Consistent positive associations were found between circulating IGF-1 and breast cancer risk for both analyses • These results support a probable causal role of the IGF pathway in breast cancer development

IntroductionMeat consumption may be associated with a higher risk of cardiovascular diseases, but the evidence remains inconclusive. We prospectively examined the association between meat (total meat, red and processed meat, red meat, processed meat and poultry) intake and risk of ischemic heart disease (IHD) and stroke, including ischemic and haemorrhagic subtypes, in a large British cohort.Materials and methodsData were from UK Biobank participants who were free of IHD, stroke and cancer at recruitment (2006–2010), with available information on meat intake in the baseline touchscreen survey, and linked hospital admissions and death data for IHD, stroke, and stroke subtypes over follow-up (n = 441,700). We used multivariable Cox proportional hazards models to assess associations between meat consumption and risk of IHD, total stroke and ischemic and haemorrhagic stroke subtypes.ResultsOver a mean of 8.1 years of follow-up, 13,590 incident cases of IHD, 5,441 cases of total stroke, 2,258, cases of ischaemic stroke, and 949 cases of haemorrhagic stroke occurred. The risk of IHD was positively associated with intakes of total meat (Hazard ratio (HR) = 1.18, 95% Confidence Interval (CI) 1.09, 1.27 per 100 g/day higher intake), red and processed meat (HR = 1.15, 95% CI 1.08, 1.24 per 70 g/day higher intake), red meat (HR = 1.15, 95%, CI 1.07–1.24 per 50 g/day higher intake), processed meat (HR = 1.11, 95% CI 1.05, 1.16 per 20 g/day higher intake), and poultry (HR = 1.07, 95% CI 1.01, 1.13 per 30 g/day higher intake). The risk of total stroke was positively associated with intakes of total meat (HR = 1.15, 95% CI 1.02–1.29 per 100 g/day higher intake) and red and processed meat (HR = 1.14, 95% CI 1.03–1.27 per 70 g/day higher intake). Meat intake was not associated with ischaemic or haemorrhagic stroke.DiscussionThis large prospective study found that any meat consumption was associated with an increased risk of IHD and that red and processed meat consumption was associated with an increased risk of total stroke. Our findings for IHD and total stroke in relation to red and processed meat are in line with previous studies but our positive findings for poultry and IHD and null findings for red meat and ischaemic stroke are not, thus warranting further study.

BackgroundEpidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses to allow causal inference.Patients and methodsWe investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206,263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6,711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGFBP-3 levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122,977 cases and 105,974 controls.ResultsIn the UK Biobank, after a median follow-up of 7.1 years, 4,360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/L increment of IGF-1=1.11, 95%CI=1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/L increment in genetically-predicted IGF-1 concentration was associated with greater breast cancer risk (odds ratio [OR]=1.05, 95%CI=1.01-1.10; Pvalue=0.02), with a similar effect estimate for estrogen positive (ER+) tumors, but no effect found for estrogen negative (ER-) tumors. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (OR per 1-SD increment=1.00, 95%CI=0.97-1.04; Pvalue=0.98).ConclusionOur results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.DisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

IntroductionDifferences in health outcomes between meat-eaters and non-meat-eaters might relate to differences in dietary intakes between these diet groups. We assessed intakes of major protein-source foods and other food groups in six groups of meat-eaters and non-meat-eaters participating in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Oxford study.Materials and methodsData were from 30, 239 participants who answered four questions regarding their consumption of meat, fish, dairy or eggs and completed a food frequency questionnaire (FFQ) in 2010. Participants were categorized as regular meat-eaters (> 50 grams of total/any meat per day: n = 12,997); low meat-eaters (< 50 grams of total/any meat per day: n = 4,650); poultry-eaters (poultry but no red meat: n = 591); fish-eaters (no meat but consumed fish: n = 4,528); vegetarians (no meat or fish: n = 6,672); and vegans (no animal products: n = 801). FFQ foods were categorised into 45 food groups. Analysis of variance was used to test for differences between age-adjusted mean intakes of each food group by diet group.ResultsWe found that regular meat-eaters, vegetarians and vegans, respectively, consumed about a third, quarter and a fifth of their total energy intake from high protein-source foods. Compared with regular meat-eaters, low and non-meat-eaters consumed higher amounts of high-protein meat alternatives (soy, legumes, pulses, nuts, seeds) and other plant-based foods (whole grains, vegetables, fruits) and lower amounts of refined grains, fried foods, alcohol, and sugar-sweetened beverages.DiscussionOverall, our results suggest that there were large differences in the amounts and types of protein-rich and other foods eaten by regular, low and non-meat-eaters. These findings provide insight into potential nutritional explanations for differences in health outcomes between diet groups.

Prospective studies have observed differences in risks for several health outcomes when comparing meat-eaters and vegetarians, but the mechanisms underlying these differences remain uncertain. Identifying genetic factors related to vegetarianism may be valuable for assessing causality. We report a genome-wide association study (GWAS) of vegetarianism in 367,198 participants from UK Biobank. We identified one locus, rs10189138, near the vaccinia related kinase 2 (VRK2) gene, significantly associated with vegetarianism (β=0.153, p=3x10-8). The associations between rs10189138 and 40 traits were calculated, and the rs10189138 T allele (MAF=0.12) was found to be significantly associated with greater height, after controlling the false discovery rate (FDR). Correlations between genetically predicted vegetarianism and 855 other genetically predicted traits were also calculated, and vegetarianism had significant positive genetic correlations with fluid intelligence and age at menarche, after controlling the FDR. Future research on an independent sample is needed to see if this GWAS result can be replicated.

Metabolomics may reveal novel insights into the etiology of prostate cancer, for which few risk factors are established. We investigated the association between patterns in baseline plasma metabolite profile and subsequent prostate cancer risk, using data from 3,057 matched case–control sets from the European Prospective Investigation into Cancer and Nutrition (EPIC). We measured 119 metabolite concentrations in plasma samples, collected on average 9.4 years before diagnosis, by mass spectrometry (AbsoluteIDQ p180 Kit, Biocrates Life Sciences AG). Metabolite patterns were identified using treelet transform, a statistical method for identification of groups of correlated metabolites. Associations of metabolite patterns with prostate cancer risk (OR1SD) were estimated by conditional logistic regression. Supplementary analyses were conducted for metabolite patterns derived using principal component analysis and for individual metabolites. Men with metabolite profiles characterized by higher concentrations of either phosphatidylcholines or hydroxysphingomyelins (OR1SD = 0.77, 95% confidence interval 0.66–0.89), acylcarnitines C18:1 and C18:2, glutamate, ornithine and taurine (OR1SD = 0.72, 0.57–0.90), or lysophosphatidylcholines (OR1SD = 0.81, 0.69–0.95) had lower risk of advanced stage prostate cancer at diagnosis, with no evidence of heterogeneity by follow‐up time. Similar associations were observed for the two former patterns with aggressive disease risk (the more aggressive subset of advanced stage), while the latter pattern was inversely related to risk of prostate cancer death (OR1SD = 0.77, 0.61–0.96). No associations were observed for prostate cancer overall or less aggressive tumor subtypes. In conclusion, metabolite patterns may be related to lower risk of more aggressive prostate tumors and prostate cancer death, and might be relevant to etiology of advanced stage prostate cancer., What's new? This prospective study is the largest investigation of metabolite profile and prostate cancer risk, to date. We found that patterns in plasma metabolite profile (characterized by higher concentrations of phosphatidylcholines and hydroxysphingomyelins; specific acylcarnitines, amino acids and a biogenic amine; and lysophosphatidylcholines, respectively) were associated with subsequent lower risk of more aggressive tumor subtypes and prostate cancer death. Moreover, the results suggest that metabolite profile may be relevant to the etiology of advanced stage disease.

Background: Prostate cancer is the most common cancer in British men but its aetiology is not well understood. We aimed to identify risk factors for prostate cancer in British males. Methods: We studied 219 335 men from the UK Biobank study who were free from cancer at baseline. Exposure data were collected at recruitment. Prostate cancer risk by the different exposures was estimated using multivariable-adjusted Cox proportional hazards models. Results: In all, 4575 incident cases of prostate cancer occurred during 5.6 years of follow-up. Prostate cancer risk was positively associated with the following: black ethnicity (hazard ratio black vs white=2.61, 95% confidence interval=2.10–3.24); having ever had a prostate-specific antigen test (1.31, 1.23–1.40); being diagnosed with an enlarged prostate (1.54, 1.38–1.71); and having a family history of prostate cancer (1.94, 1.77–2.13). Conversely, Asian ethnicity (Asian vs white hazard ratio=0.62, 0.47–0.83), excess adiposity (body mass index (⩾35 vs

Background: Human metabolism is influenced by dietary factors and lifestyle, environmental, and genetic factors; thus, men who exclude some or all animal products from their diet might have different metabolic profiles than meat eaters. Objective: We aimed to investigate differences in concentrations of 118 circulating metabolites, including acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, and sphingolipids related to lipid, protein, and carbohydrate metabolism between male meat eaters, fish eaters, vegetarians, and vegans from the Oxford arm of the European Prospective Investigation into Cancer and Nutrition. Design: In this cross-sectional study, concentrations of metabolites were measured by mass spectrometry in plasma from 379 men categorized according to their diet group. Differences in mean metabolite concentrations across diet groups were tested by using ANOVA, and a false discovery rate–controlling procedure was used to account for multiple testing. Principal component analysis was used to investigate patterns in metabolic profiles. Results: Concentrations of 79% of metabolites differed significantly by diet group. In the vast majority of these cases, vegans had the lowest concentration, whereas meat eaters most often had the highest concentrations of the acylcarnitines, glycerophospholipids, and sphingolipids, and fish eaters or vegetarians most often had the highest concentrations of the amino acids and a biogenic amine. A clear separation between patterns in the metabolic profiles of the 4 diet groups was seen, with vegans being noticeably different from the other groups because of lower concentrations of some glycerophospholipids and sphingolipids. Conclusions: Metabolic profiles in plasma could effectively differentiate between men from different habitual diet groups, especially vegan men compared with men who consume animal products. The difference in metabolic profiles was mainly explained by the lower concentrations of glycerophospholipids and sphingolipids in vegans.